Biomedical polymer materials are subject to property requirements that may be discussed in terms of bulk property requirements and surface property requirements. The bulk properties must afford a particular medical device with the mechanical characteristics, such as flexibility, toughness, fracture-resistance, tensile strength, etc., needed for a particular application, while the surface properties relate to the biocompatibility of the material with interfacial bodily fluids or tissue. For example, the desired surface properties of a device in contact with blood or tissue may generally include thrombo-resistance, infection-resistance, anti-adhesion or adhesion-promoting properties, lubricious properties, and/or non-inflammatory properties.
Approaches to modifying the surface of a biostable polymer substrate at least partially covering an implantable unit of a medical device include using surface-modifying additives or surface-active endgroups. Polymeric compositions of linear base polymers having covalently bonded surface-active endgroups are disclosed in U.S. Pat. No. 5,589,563 and in International publication WO 02/085425, both of which, in their entireties, are incorporated herein.
Another general approach to achieving improved biocompatibility is to use bioactive coatings. For example anti-thrombogenic, anti-infection, anti-inflammatory or other bioactive agents may be applied to a polymer surface. Bioactive agents may be ionically bound to a polymeric surface, however, once exposed to blood and bodily fluids, the bioactive molecules bonded in this way may leach away from the surface such that only a transient effect is realized. Bioactive agents may also be covalently bonded to the polymer backbone of the substrate. The bioactive agent may be better immobilized on the polymer substrate by covalent bonding but generally loses its desired effect to some degree because the bioactive molecule has fewer available functional binding sites, reduced mobility, and limited interaction with physiological substrates. An implantable medical device coated with a bioactive material could be improved if the release of the bioactive agent occurred only when needed to combat thrombogenic, inflammatory, or other cellular responses.
One type of implantable unit includes medical electrical leads used for stimulating excitable body tissue for therapeutic purposes such as cardiac pacing, pain control, restoring or reconditioning muscular function, and other purposes. The safety and efficacy of such therapies depends, in part, on the performance of the associated medical lead(s). One factor that can affect lead performance, particularly during the first several weeks after implantation of a lead, is the natural inflammatory response of the body to the lead as a foreign object. The presence of the lead (or other type of implantable medical device) activates macrophages, which attach themselves to the surface of the lead and any electrodes. Some macrophages form multi-nucleated, foreign body giant cells (FBGCs). Macrophages and FBGCs, in turn, secrete various substances, such as hydrogen peroxide as well as various lysosomal enzymes and oxidants, in an effort to break down the foreign object such that the macrophages and FBGCs are able to phagocytose the foreign object. When phagocytosis of the foreign body fails, activated macrophages attract fibroblasts (by chemotaxis) and activate them to lay down a collagenous tissue capsule. This capsule separates the foreign body from the surrounding tissue. Resident macrophages and fibroblasts within the capsule may continue to secrete enzymes for a prolonged period of time, producing a chronic inflammatory response.
Several effects of the acute and chronic inflammatory responses can adversely affect medical lead reliability in regard to both electrode performance and chronic stability of the insulation of lead conductors. At an electrode site, the acute inflammatory response around an electrode surface, can inflict damage to adjacent muscle tissue. Damaged tissue closest to the electrode becomes necrotic. Necrosis provokes further inflammation to exacerbate the tissue damage, significantly increasing acute stimulation thresholds. Chronic stimulation thresholds may be elevated by the development of a collagenous tissue capsule formed around the electrode site. The capsule is not excitable, resulting in an elevated stimulation threshold due to the degraded electrical properties of the electrode-tissue interface.
The insulated portions of a medical lead may also be adversely affected by the foreign body response and chronic inflammation. In the case of cardiac leads, a transvenous lead body, which is implanted in blood, can cause thrombus formation, even if the surface is non-thrombogenic, due to blood stasis or endothelial injury. If the thrombus is in contact with the endothelium, macrophages can invade the clot, phagocytose the blood cells and orchestrate collagenous encapsulation by fibroblasts to stabilize the clot. The foreign body response is initiated with the adhesion and activation of macrophages on the lead body surface, with the subsequent release of oxidants and enzymes intended for breaking down the foreign body. Prolonged exposure to secreted lysosomal oxidants can damage the polymeric insulation of the medical lead in a process known as “environmental stress cracking.” Adhesion between the lead and collagenous capsule make lead removal difficult if the lead ever needs to be repositioned or removed.
To address the problems associated with inflammation and the foreign body response at the electrode site, steroid-eluting leads have been introduced. A steroid-eluting porous pacing electrode is generally disclosed in U.S. Pat. No. 4,506,680, issued to Stokes, and related, commonly assigned, U.S. Pat. Nos. 4,577,642 and 4,606,118, all incorporated herein by reference. A water-soluble, anti-inflammatory steroid is retained in a cavity within the lead, preferably in a polymer carrier mounted within a cavity of a tip electrode, and is exposed to body fluids through a porous elution path. A method for coating an electrode with a steroid that is no more than sparingly soluble in water is generally disclosed in U.S. Pat. No. 5,987,746 issued to Williams, incorporated herein by reference in its entirety. The Capsure Z™, Model 5534, steroid-eluting lead available from Medtronic, Inc., includes a tip electrode fabricated of platinized porous platinum deposited with the water soluble steroid dexamethasone sodium phosphate and equipped with a monolithic controlled release device (MCRD) within a cavity of the electrode loaded with the water soluble steroid. Steroid eluting leads present significantly lower peak and chronic stimulation thresholds than non-steroid eluting leads having similarly sized electrodes.
While improving electrode performance, steroid elution near the electrode site does little to prevent encapsulation and environmental stress cracking along the lead body insulation. Elution of a bioactive agent along the entire length or even portions of a medical lead, however, may result in release of an undesired systemic dosage. Furthermore, encapsulation of a lead body in the blood stream may not occur for many years, not until a thrombus forms. (See Stokes K, Anderson J, McVenes R, McClay C. “The encapsulation of transvenous polyurethane insulated cardiac pacemaker leads,” Cardiovascular Pathology, 4(3):163-172, 1995.) Elution of a bioactive agent in the first weeks after implant would not prevent a late-occurring foreign body response.
It is desirable, therefore, to provide a bioactive composition for use with medical electrical leads, or other types of implantable units of medical devices, which will modify the cellular inflammatory response when it occurs. Since the exact timing of the initiation of a foreign body response is unpredictable, a composition that allows extraction or elution of a bioactive agent at the initiation of the foreign body response is needed. A bioactive composition that improves medical lead performance by reducing or halting the foreign body response and thereby prevents environmental stress cracking, reduces adhesion to ease removability, and/or maintains low stimulation thresholds is desired.